Yang H Y, Zhou B P, Hung M C, Lee M H
Departments of Molecular Cellular Oncology and Surgical Oncology, Breast Cancer Research Program, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
J Biol Chem. 2000 Aug 11;275(32):24735-9. doi: 10.1074/jbc.C000147200.
Overexpression and activation of HER-2/neu, a proto-oncogene, play a pivotal role in cancer formation. Strong expression of HER-2/neu in cancers has been associated with poor prognosis. Reduced expression of p27(Kip1), a cyclin-dependent kinase inhibitor, correlates with poor clinical outcome in many types of carcinomas. Because many cancers with the overexpression of HER-2/neu overlap with those affected by reduced p27 expression, we studied the link between HER-2/neu oncogenic signals and p27 regulation. We found that down-regulation of p27 correlates with HER-2/neu overexpression. To address the molecular mechanism of this inverse correlation, we found that reduction of p27 is caused by enhanced ubiquitin-mediated degradation, and the HER-2/Grb2/MAPK pathway is involved in the decrease of p27 stability. Also, HER-2/neu activity causes mislocation of p27 and Jun activation domain-binding protein 1 (JAB1), an exporter of p27, into the cytoplasm, thereby facilitating p27 degradation. These results reveal that HER-2/neu signals reduce p27 stability and thus present potential points for therapeutic intervention in HER-2/neu-associated cancers.
原癌基因HER-2/neu的过表达和激活在癌症形成中起关键作用。HER-2/neu在癌症中的强表达与预后不良相关。细胞周期蛋白依赖性激酶抑制剂p27（Kip1）的表达降低与多种类型的癌症患者临床预后不良相关。由于许多HER-2/neu过表达的癌症与p27表达降低的癌症重叠，我们研究了HER-2/neu致癌信号与p27调控之间的联系。我们发现p27的下调与HER-2/neu的过表达相关。为了探究这种负相关的分子机制，我们发现p27的减少是由泛素介导的降解增强所致，并且HER-2/Grb2/MAPK信号通路参与了p27稳定性的降低。此外，HER-2/neu的活性导致p27和p27的输出蛋白Jun激活域结合蛋白1（JAB1）错位到细胞质中，从而促进p27的降解。这些结果表明，HER-2/neu信号降低了p27的稳定性，因此为HER-2/neu相关癌症的治疗干预提供了潜在靶点。
